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Cell Rep DOI:10.1016/j.celrep.2013.12.007

S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury.

Publication TypeJournal Article
Year of Publication2014
AuthorsCox, AG, Saunders, DC, Kelsey, PB, Conway, AA, Tesmenitsky, Y, Marchini, JF, Brown, KK, Stamler, JS, Colagiovanni, DB, Rosenthal, GJ, Croce, KJ, North, TE, Goessling, W
JournalCell Rep
Volume6
Issue1
Pages56-69
Date Published2014 Jan 16
ISSN2211-1247
KeywordsAcetaminophen, Aldehyde Oxidoreductases, Animals, Chemical and Drug Induced Liver Injury, Liver, Mice, Mice, Inbred C57BL, NF-E2-Related Factor 2, Nitric Oxide, Nitric Oxide Donors, S-Nitrosothiols, Zebrafish, Zebrafish Proteins
Abstract

Toxic liver injury is a leading cause of liver failure and death because of the organ's inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo; in zebrafish, nitric-oxide (NO) enhanced liver formation independently of cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition of the enzymatic regulator S-nitrosoglutathione reductase (GSNOR) minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted with the approved therapy N-acetylcysteine to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates for treating liver injury.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S2211-1247(13)00752-3
DOI10.1016/j.celrep.2013.12.007
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24388745?dopt=Abstract

Alternate JournalCell Rep
PubMed ID24388745
PubMed Central IDPMC4008725
Grant ListR01 DK090311 / DK / NIDDK NIH HHS / United States
DK090311 / DK / NIDDK NIH HHS / United States